It is estimated that addiction and its associated costs: crime, domestic violence and child abuse, health care costs, and loss of employment and family structure, exceed half of a trillion dollars per year. A major barrier to successful treatment of a estimated 20 million Americans suffering from addiction is the lack of understanding of factors important for drug seeking, withdrawal and reinstatement (relapse). One such factor, brain-derived neurotrophic factor (BDNF) has long been recognized as a critical trophic factor for the growth, development and survival of developing neurons as well as for mediating synaptic transmission and synaptic plasticity. In recent years, however, BDNF has been strongly implicated in a number of neuropsychiatric disorders, including drug addiction, depression, bipolar disorders, and schizophrenia. The rat is the preferred rodent model in the field for understanding behavior and could serve as a powerful preclinical model for investigating the role of BDNF in these disorders, however, the tools for manipulating rat genes have historically been lacking. Our group has recently developed a number of tools to overcome this barrier, creating the world's first gene knockout rats and developing new and efficient transgenic techniques. We propose to adapt these innovative methods to generate transgenic rats where expression levels of BDNF, or other genes, can be fine-tuned in a spatial and temporal manner. These novel rat models will be the first animal models of their kind to address the role of BDNF in addiction behavior. An innovative aspect of the design of these transgenic animals will also allow easy exchange of genes of interest, promoters, and reporter genes to tailor the needs of many different NIDA investigators in the future. The current proposal has two specific aims: Aim 1 is to generate rats with flexible transgenes to allow conditional and inducible gene knockdown in rats via RNA interference, focusing on BDNF as our first example. These transgenic lines will be useful to many researchers investigating drug addiction, affective disorders, and other neurological diseases. Aim 2 is to characterize the effects of BDNF knockdown on addiction-related behavior in an established rat paradigm of cocaine addiction. Our hypothesis is that BDNF knockdown will selectively reduce BDNF expression in adult neurons, leading to abnormal neurochemical and behavioral responses to cocaine administration, withdrawal, and reinstatement. We have assembled a collaborative and productive team of investigators to deploy these tools and to determine the impact of reduced forebrain levels of BDNF on cocaine-induced reinstatement in transgenic rats. Once established, these rat models and methodologies will be made available to all interested researchers in the neuroscience community.